Susan Buckles (@susanbuckles)

As many as 25 million Americans – about 1 in 13 people – suffer from a rare, undiagnosed condition.* April 29 has been designated Undiagnosed Disease Day to raise awareness that collectively, rare diseases are relatively common. People with a rare disease often spend years visiting different medical providers and clinics seeking answers to unexplained conditions. Mayo Clinic Center for Individualized Medicine brings together a team of experts, the most sophisticated genomic testing and worldwide research to solve complex, undiagnosed cases.

Genetic sleuthing of puzzling cases

The Human Genome Project —the first mapping of a person’s genetic blueprint — has unlocked mysteries of rare diseases that for ages bewildered medical science. Completed just 16 years ago, the Human Genome Project has ushered in a new era of individualized medicine that has significantly advanced the ability to diagnose rare, genetic diseases.

The Center for Individualized Medicine’s experts, who make up the Genomic Odyssey Board, consult clinical findings, DNA testing and research to solve rare disorders. Patients come from around the world seeking a diagnosis. DNA testing offers a genetic trail of clues that sometimes leads researchers and clinicians to a scientific pot of gold: a diagnosis that no one else has been able to make. Even if there’s not a treatment, having a diagnosis can be life changing. Patients can stop spending time and money visiting countless health care providers in search of answers.

Mayo Clinic has been able to diagnose approximately 30 percent of patients with unexplained genetic disorders. The Genomic Odyssey Board would like to close the gap on the other 70 percent of cases that go unsolved, and advancements in tools offer hope for a better success rate.

Dr. Heidi Rehm: Data sharing brings new answers for everyone.

The promise of DNA sequencing also brings the challenge of interpreting big data. Consider this: sequencing one patient’s genome generates data so massive that if stacked end-to-end, it would reach from earth to the moon. Finding disease-related genetic variants within those results can be like looking for a needle in a haystack.

Heidi Rehm, Ph.D., a geneticist and genomic medicine researcher at the Broad Institute Chief Genomics Officer at Massachusetts’s General Hospital and Professor of Pathology and Harvard Medical School, has called for broader knowledge sharing of disease-related variants in order to zero in on disease-causing genes.

“It’s a combination of crowd sourcing the challenge, sharing the evidence, identifying when we might view evidence differently, and validating the findings,” says Dr. Rehm. “If we’re really going to integrate genetics into the practice of medicine, we need to ensure that the information we are returning to patients is valuable and accurate. We need resource sharing across the community to do that.”

Dr. Rehm identified three key genomic data sharing sites that are improving the chances of finding a diagnosis:

• ClinGen – a large NIH program that develops standards and assembles experts to compile and review evidence and for assessing the role of genes and variants in disease.

• Matchmaker Exchange – a platform for building evidence for genes implicated, but not proven to be linked to disease.

Information from data sharing sites helped establish best practices in genetic and genomic testing, leading to more reliable and consistent results.

“This means patients are more likely to have their disease-causing variants identified as causal rather than classified as a variant of uncertain significance. As a result, they are more likely to get an accurate and consistent diagnosis that stands up to testing from multiple labs,” says Dr. Rehm.

Dr. Eric Klee: New tools and new technology on the horizon

Mayo Clinic is developing computer software that would analyze genetic data from unsolved cases in which the trail has gone cold. The software program would send alerts when new research reveals understanding of a gene that could crack a case.

“We are in a unique timeframe in the history of mankind in that we are learning exponentially more all the time about genetic disease. What we know today is so drastically different from what we knew even a year ago,” says Dr. Klee. “Tools that allow us to automatically go back and analyze cases in terms of new knowledge are going to be very important.”

Dr. Klee, who also presented at the 2018 Individualizing Medicine Conference, envisions new tools that would broaden data sharing to include both genotype (genetics) and phenotype (visible characteristics such height, eye color, overall health status and disease history) in a centralized, worldwide database.

“That unleashes the power of experts from around the world to solve rare cases rather than just from one institution,” says Dr. Klee. “The ability to learn and diagnose would be significantly improved.”

On the technology side, Dr. Klee predicts whole genome sequencing — which covers all a person’s DNA — will replace the current practice of sequencing only the known disease causing genes. That will give investigators additional information on how changes within the genetic blueprint might be causing disease. He believes RNA sequencing, which reveals defects within the genes, will also be increasingly used. That may improve the solve rate for patients who are seeking a diagnosis after suffering for years from an unknown disease.

March is Colorectal Cancer Awareness Month, a time to focus on one of the most common and preventable forms of cancer. Mayo Clinic is applying a new genomic lens to colorectal and other cancers to identify which are the types that run in families. The answer to that could open new treatment options and also take the guess work out of who else in your family is at higher risk for cancer.

Niloy “Jewel” Samadder, M.D., a gastroenterologist at Mayo Clinic’s Arizona campus, is leading efforts to usher in a new era of screening and detection that focuses on identifying hereditary cancers. Research shows that 1 in every 15 cases of colon cancer and possibly up to 1 in every 5 cases of cancer overall are linked to underlying inherited genetic mutations.

A diagnosis of hereditary cancer often changes treatment to an individualized approach shaped by a patient’s genetic makeup. Mayo Clinic, with the support of the Center for Individualized Medicine, is moving toward testing all cancer patients for such inherited mutations — not just patients with cancer in their family tree.

Niloy “Jewel” Samadder, M.D.

“If we know that cancer was genetically predisposed, it can lead to unique options ensuring that treatments target the cancer and minimize side effects,” says Dr. Samadder. “For example, research shows that certain targeted chemotherapies and immunotherapies are not specific to the type of tumor or cancer but really act on certain molecular pathways. So, whether that cancer is colon, prostate or breast, we can respond with a drug that is targeted to the genetic mutations that caused that cancer rather than a specific tumor.”

To identify hereditary cancer, Mayo uses a robust DNA blood test panel that examines genes known to have links to cancer.

“This is the most comprehensive cancer genetic panel available today,” says Dr. Samadder. “We believe this gives us the tools for catching and treating inherited cancers that might have gone undetected in the past.”

If this test finds you have an inherited cancer, there is a 50 percent chance your immediate family members have the same genetic alteration that would increase their chance of developing a similar cancer. Under current cancer screening guidelines, up to half of all inherited cancers go undetected — a missed opportunity for early detection and possibly even cancer prevention.

Those with a genetic predisposition face a greater than average lifetime risk for cancer, but it is not 100 percent certain they would develop the disease. Lifestyle and environment also play a role in cancer risk.

Prevent a second cancer

Keila Alvarado of Phoenix was diagnosed with rectal cancer in 2008 at the age of 32. Genetic testing revealed Lynch syndrome, a hereditary condition that puts her at higher risk of developing colon, ovarian, uterine, stomach and other cancers.

Keila Alvarado

“I was surprised. I really didn’t understand much about genetics at the time. I’m happy to have this information, because it’s better to be prepared. I now understand my risk for future cancers,” says Alvarado.

With grit and determination, Ms. Alvarado fought rectal cancer with surgery, chemotherapy and radiation. Now in remission, she has turned her attention to a new challenge: preventing a second type of cancer related to Lynch syndrome. She’s had a pre-emptive hysterectomy, has yearly blood work and screenings and is vigilant about her health.

“Any time the doctor says this is a preventive measure, I’m like, ‘ya, let’s do it.’ I don’t mind the different tests. I also take seriously my intake of food and how I can eat healthier. I try to be conscious of what I do and live a healthy lifestyle,” she says.

Now others in Alvarado’s family know they, too, could be at risk of inherited mutations that put them at higher risk for cancer. Some family members have chosen to have genetic testing, and those who also tested positive for Lynch syndrome can take a proactive approach to prevention.

“For patients with Lynch Syndrome, we suggest earlier and more frequent screenings. We recommend the first colonoscopy at age 20 and then once every one to two years after that. That’s different from the normal population where we start at age 50 and test every five to 10 years after that. We also recommend more frequent imaging, blood work, urine tests and skin exams,” Dr. Samadder says. “We would also refer females to a gynecologist to monitor for risks of uterine and ovarian cancer — possibly even recommending pre-emptive surgery.”

In some cases, Mayo will refer patients for chromoendoscopy, an ultra-sensitive screening which applies a special stain during a colonoscopy to detect polyps that might have otherwise been missed.

Dr. Samadder says Keila Alvarado’s case is a great example of how a new era of genetic screening can help inform family members who might not have known they are at higher risk of cancer. They can respond proactively to try to prevent cancer or catch it an early stage when it is curable.

For people with a rare genetic disease, the path to a diagnosis can be a long, costly and painful journey. Often times, answers to unexplained conditions go undetected, because the underlying cause lies deep within a person’s genetic code, inaccessible to standard laboratory testing. Whole genome sequencing may unlock those answers by providing the most comprehensive examination of a person’s DNA for genetic changes that are driving disease. But to date, patients have had limited access to whole genome sequencing. The testing is offered at only select laboratories, and it is not always covered by insurance.

Eight leading health care and research organizations in the United States and Canada, including Mayo Clinic, are collaborating to make whole genome sequencing more accessible to patients in clinical care. Together they have launched the Medical Genome Initiative to expand access to patients and health care facilities.

Read the news release about the launch of the Medical Genome Initiative.

Hutton Kearney, Ph.D.

“Whole genome sequencing is the most comprehensive approach for evaluating the human genome for the cause of genetic diseases,” says Hutton Kearney, Ph.D., director of the Genomics Laboratory, Mayo Clinic Department of Laboratory Medicine and Pathology. “With whole genome sequencing, we can find more answers for more patients.”

The Medical Genome Initiative will bring together experts in DNA sequencing technology, bioinformatics and data handling, clinical interpretive approaches, health care policy and research. With an eye on establishing best practices, leaders of this initiative hope to make whole genome sequencing more affordable and efficient so more patients can have access to this high quality test.

“We will also work to define quality and performance expectations for clinical whole genome sequencing, especially as it relates to comparisons to other gold standard assays. Our efforts will inform appropriate ordering practices and help to maximize the diagnostic opportunity and clinical impact of this comprehensive testing,” says Dr. Kearney.

Have you ever wondered why some people can eat all they want and never gain weight while others exercise and watch what they eat but still can’t shed a pound? The clue may lie partly in your gut microbiome, the complex community of bacteria within the digestive tract that is genetically different in each person.

A personalized diet based on your microbiome, genetics, age and activity level is a better way to control your blood glucose (sugar) than cutting carbohydrates and calories, according to research from the Mayo Clinic Center for Individualized Medicine. Glucose is the main source of energy for the body, but too much blood sugar is stored as fat. Managing blood sugar is therefore important to controlling weight and preventing conditions such as diabetes, heart disease and kidney disease.

Helena Mendes Soares, Ph.D.

“Our research shows that everyone responds differently to foods. We found that the standard approach of counting carbohydrates and calories alone is not the best approach to managing blood sugar, because it only takes into account characteristics of food. It fails to recognize that each person’s unique lifestyle, demographics and microbiome also play a role,” says Helena Mendes Soares, Ph.D., a scientist within the Mayo Clinic Microbiome Program and the lead author on the study.

“With our individualized model, you don’t have to give up all high fat or high carb foods, as previously thought. You can choose specific foods within those categories that work well with your own genetic makeup and microbiome. For example, I discovered that apples cause my blood sugar to spike, but pears do not. Instead of giving up all fruits, I can personalize my diet with foods based on my physiology, lifestyle and microbiome.”

The research

Vivek Iyer, M.D., a critical care physician at Mayo Clinic was looking for scientifically-based tips to help him control his weight. Dr. Iyer was one of 327 people who enrolled in a Mayo Clinic study of glycemic responses to food. For six days, participants had a standard breakfast of bagels and cream cheese and ate what they wanted the rest of the day. They kept a log of their meals, exercise and rest while a glucose monitor tracked blood sugar levels. Each participant submitted a stool sample that was genetically sequenced to learn what foods worked well with their microbiomes.

Vivek Iyer, M.D.

“It helped me understand how my body responds to different foods. After eating the breakfast bagel, my blood sugars shot up and stayed there for several hours. Refined sugars and processed carbohydrates seemed to be the culprits. Other carbohydrates and foods higher in proteins and fats tended to be better for my blood sugar level,” says Dr. Iyer.

With this knowledge, Dr. Iyer took a personalized approach to modifying his diet.

“I don’t have to give up all carbohydrates. Instead, I’ve cut down on just the carbohydrates that cause my blood sugar to rise, like rice and wheat grains. I am eating more proteins such as eggs and cottage cheese that keep my blood sugar steady. And I’m staying away from sugary breakfast cereals and yogurts. I’ve lost a little bit of weight and I feel more energetic,” he says.

Role of the microbiome

Mayo researchers say their model, which accounts for age, lifestyle and genetic differences in each person’s microbiome, accurately predicted blood sugar response to food 62 percent of the time. That is far superior to the 40 percent accuracy for predictions based on carbohydrates alone and 32 percent based on calories alone.

Purna Kashyap, M.B.B.S.

“The clever thing about this approach is that it’s adjusting your diet to your microbiome, rather than trying to change the bacteria in your microbiome – which could take time. Our model allows you to look at the diet to learn which foods will work best with the microbiome when considering a biological outcome, which in this case was blood glucose,” says Purna Kashyap, M.B.B.S., the Bernard and Edith Waterman co-director of the Center for Individualized Medicine Microbiome Program and an author on the study.

Researchers say these findings are the first step toward validating the health benefits of personalized diets. This research confirmed conclusions of a similar study conducted at the Weizmann Institute of Science in Israel.

January is Cervical Health Awareness Month, a time to reflect on personalized approaches to preventing or treating cervical cancer.

Harrowing stories of rampant sexual violence and high instances of cervical cancer in the Democratic Republic of Congo spurred Marina Walther-Antonio, Ph.D. to action. The emotional stories of survival and death triggered her desire to discover a tool that could transform cancer screening for women from Africa to America and beyond.

Marina Walther-Antonio, Ph.D.

“I asked, ‘what can I do? I was surprised to hear that the greatest need was for research. That’s right in my wheelhouse,” says Dr. Walther-Antonio, a researcher within the Mayo Clinic Center for Individualized Medicine who has a joint appointment in the Mayo Clinic Department of Obstetrics and Gynecology. “They (African providers) wanted a test that could detect cancer early — something African women could do themselves at home, so they wouldn’t have to travel a long, risky journey to a hospital for cancer screening.”

Dr. Walther-Antonio galvanized her research team to develop a low cost, easy-to-use test that could screen for human papillomavirus (HPV). A positive test for certain strains of HPV could be an early signal of cervical cancer. Their goal is to keep the cost to under $2 per test, affordable enough to be used in a mobile campaign that would promote HPV screening in the Democratic Republic of Congo.

Like a home pregnancy test

Dr. Walther-Antonio’s team envisions the tool similar in concept to a home pregnancy test, although the chemical composition would be different. The user would use a urine sample in a simple mix-rinse-read procedure. If the marker turns blue, the person is a carrier of a high-risk HPV strain. If the test is negative, the marker will be clear.

“We want the user to easily understand whether the results are negative or positive without needing a lab test or a physician to interpret. It could cut down on the number of trips to the hospital. People would not have to go in to be screened and would have to be seen only if their test is positive,” adds Dr. Walther-Antonio. “The test is based on genetics, but the genetics of HPV rather than that of the patient. It has the same genetic targets as a PCR-based test, but without the need for lab facilities or expert handling.”

Interest in the United States

While still in the testing and development phase, Dr. Walther-Antonio’s screening tool has generated interest in the United States and beyond.

“This could be extremely useful for low-income women who don’t have easy access to medical care. It could improve cervical cancer screening rates and increase the frequency of screening,” says Dr. Walther-Antonio.

And, the research is exploring whether a similar type of test could be used to detect other disease targets including:

High-risk HPV strains in saliva for oropharyngeal cancer screening

Antibiotic resistant E. Coli

Flu virus

The HPV screening tool is still in early testing, where they are seeking improvements such as increasing shelf life. It could take several years before the tool moves on to the next stage of testing and eventually clinical trials.

Early cancer screening tools have helped improve cervical cancer diagnosis and treatment, which has decreased the number of cervical cancer deaths. More than 13,000 women in America will be diagnosed with cervical cancer this year, and it’s estimated that 4,250 will die of the disease.

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“For decades, we thought that kidney stones formed in a slow, steady, layer-by-layer process like dust settling in your house. However, new high-resolution cross sections of these stones indicate they repeatedly grow and dissolve on their way to becoming a fully formed stone. There are periods of rapid growth, large missing gaps and dissolution — it’s a back-and-forth process. This suggests that stones grow over time in a more complicated way than we previously knew, and that there may be new ways to prevent them,” says Nicholas Chia, Ph.D., co-director of the Mayo Clinic Center for Individualized Medicine Microbiome program. “We are very excited because we see the same types of patterns in kidney stones, Yellowstone rocks and many other environments on Earth.”

The kidney stone studies bring together geobiologists, microbiologists and nephrologists to prove their theory. The smoking gun, Dr. Chia says, would be a discovery that microbes — common bacteria — are driving kidney stone formation in the same way they do in Yellowstone hot spring deposits.

Kidney stone cross section

“We believe stone formation is microbially driven in the human body as well. We are trying to extract and genetically sequence the microbes and proteins that are present to figure out where they are in the stone and what processes they are responsible for,” says Dr. Chia. “We hope to answer this in future studies.”

Kidney stones are hard rocklike masses of mineral and acid salts often smaller than the head of a nail that lodge in the kidney and don’t dissolve. The only way to get rid of them is through painful urine passage or surgery.

The team is now working to understand how proteins and other biomolecules derived from both the kidney and the microbiome — the community of bacteria in your body — could lead to an eventual treatment. That’s especially important for people who follow medical advice and yet repeatedly suffer from kidney stones.

Yellowstone cross section

“If we understood the process of repeated crystallization and dissolution within kidney stones, we might be able to prescribe something that either dramatically slows the stone growth or significantly increases the disintegration. If we understood the diversity of microbes involved and their metabolic activity, we might be able to change the rates at which stones growth and dissolve, just as has been proven by research in Yellowstone hot springs. There are many options once we understand this process,” adds Dr. Chia.

Dr. Chia’s team has been working on these studies for approximately five years. He believes it will take a few more years of team science research to fully understand the combined role of the microbiome, renal (kidney) physiology and urine chemistry in growing and dissolving kidney stones.

Up to a half-million people a year visit the emergency room to seek relief from this condition, according to The National Kidney Foundation. Kidney stones are often associated with other disorders such as high blood pressure, diabetes and obesity.

Dr. Chia is the Bernard and Edith Waterman co-director of the Mayo Clinic Center for Individualized Medicine Microbiome Program.

Prostate cancer is the most common form of cancer in American men, other than skin cancer.* Statistics from the American Cancer Society show approximately 1 in 9 American men will be diagnosed with prostate cancer at some time in their lives. Mayo Clinic Center for Individualized Medicine-sponsored research released today may help families facing difficult treatment decisions.

Genetic alterations in low-risk prostate cancer diagnosed by needle biopsy can identify men that harbor higher-risk cancer in their prostate glands, Mayo Clinic has discovered. The research, which is published in the January edition of Mayo Clinic Proceedings, found for the first time that genetic alterations associated with intermediate- and high-risk prostate cancer also may be present in some cases of low-risk prostate cancers.

The study found the needle biopsy procedure may miss higher-risk cancer that increases the risk of disease progression. Researchers say that men diagnosed with low-risk cancer may benefit from additional testing for these chromosomal alterations.

George Vasmatzis, Ph.D.

“We have discovered new molecular markers that can help guide men in their decisions about the course of their prostate cancer care,” says George Vasmatzis, Ph.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and lead author on the study. “Overtreatment has been issue for the group of men that our study targets. We found that the presence of genetic alterations in low-risk cancer can help men decide whether treatment or active surveillance is right for them.”

Prostate cancer is assessed by Gleason patterns and score that indicate grade. The Gleason patterns are strongly associated with risk of disease progression. Gleason pattern 3 prostate cancer is considered to be low-risk. Gleason patterns 4 and 5 cancer carry a higher risk of aggressive behavior.

Men whose tumor is composed entirely of Gleason pattern 3 may choose active surveillance. They are monitored closely with blood tests and needle biopsies, as necessary. Or they may be referred to treatment, such as surgery and radiation, particularly if they have Gleason pattern 4 or 5.

Men with a low-risk cancer sometimes choose surgery because they don’t want to risk disease progression. The study found that men who do not have these alterations in their cancers have a low risk of harboring aggressive disease. These men may feel more comfortable choosing active surveillance. Alternatively, if a man’s low-risk tumor shows these alterations, they have a higher risk that their cancer may progress. They may consider treatment, including surgery.

The research

Researchers performed DNA sequencing with a high-tech genomic tool known as mate-pair sequencing. This research was performed on specific Gleason patterns from frozen cancer specimens from 126 men who had their prostate glands removed. They found five genes are more frequently altered in Gleason patterns 4 and 5. These alterations were found more commonly in Gleason pattern 3 associated with higher Gleason patterns and not when Gleason pattern 3 was found alone.

John Cheville, M.D.

“The needle biopsy procedure samples only a small portion of the tumor. It is not uncommon that a man with a Gleason pattern 3 on needle biopsy specimen harbors a higher-grade cancer next to the pattern 3 that was missed by the procedure,” says John Cheville, M.D., co-director of the Center for Individualized Medicine Biomarker Discovery Program and co-author of the study. “Therefore, if we identify these alterations in a Gleason pattern 3, there is a higher likelihood that Gleason pattern 4 is nearby.”

Researchers took the genetic information generated using mate pair sequencing and converted it into a test called “fluorescence in situ hybridization” (FISH) that validated the genetic alterations in clinical samples. The FISH test is available for Mayo patients.

Thank you for taking the time to comment. This article neither promotes nor discourages the eating of yogurt. The key message here is that the benefit of probiotics for specific disease states is still under investigation and there are currently no FDA approved probiotics to treat disease. Further, there is little known about the long term effects of probiotics. Dr. Kashyap recommends consulting your personal medical provider before taking probiotics for health reasons. With regards to yogurt, it is a food group that naturally has bacteria in addition to other nutrients and may have health benefits but is not meant to treat a disease.